Androsteno-2{40 ,5{40 -dimethyl-5{40 -alkyl-1{40 -pyrrolines, methods for their manufacture, and novel 16{60 (1{40 -amino-1{40 -alkylethyl)-pregnene intermediates produced thereby

ABSTRACT

Androsteno-(17 Alpha ,16 Alpha -c)-2&#39;&#39;,5&#39;&#39;-dimethyl-5&#39;&#39;-alkyl-1&#39;&#39;pyrrolines, active as mild stimulants, are prepared by reacting a 16-dehydropregnen-20-one with a disubstituted methylamine in the presence of light followed by treatment of the resulting 16 Alpha -(1&#39;&#39;-amino-1&#39;&#39;-alkylethyl)-pregnen-20-one (which per se exhibit pharmacological activity) with a secondary or tertiary amine in a lower alkanoic acid.

United States Patent Popper I ANDROSTENO-2',5'-DIMETHYL-5 ALKYLJ '-PYRROLINES, METHODS FOR THEIR MANUFACTURE, AND NOVEL 16 ALPHA-(1'-AMlN0-1 ALKYLETHYL)-PREGNENE INTERMEDIATES PRODUCED THEREBY [72] Inventor: Thomas L. Popper, 152A Linn Drive, Verona, NJ. 07044 221 Filed: Feb. 18, 1971 21 Appl.No.: 116,663

[52] US. Cl. ..260l239.5, 204/158, 260/397.3,

260/397.4, 260/999 [51] Int. Cl ..C07c 173/10 [58] Field of Search .JMachine Searched Steroids [56] References Cited UNITED STATES PATENTS [451 Aug. 15, 1972 2,750,380 6/1956 Dodson et al ....260/239.5 3,183,252 5/1965 Crabbe ..260/397.4 3,196,149 7/1965 Weiss et al ..260/239.5

Primary Examiner-Henry A. French Attorney-Stephen B. Coan and Mary S. King ABSTRACT 18 Claims, No Drawings FIELD OF INVENTION This invention relates to novel compositions-ofmatter, to methods for their manufacture, and to novel intermediates produced thereby.

More specifically, this invention relates to novel androsteno-[ I 70:, l6a-c]-2' ,5 '-dirnethyI-5 "alkyH '-pyrrolines which are mild stimulants, to methods for their manufacture, and to novel l6a-( l -amino-1'-alkylethyl)-pregnene intermediates produced thereby which also exhibit pharmacological properties per se, having antibacterial, hypotensive, and anti-inflammatory activities.

DESCRIPTION OF PRIOR ART by a multi-step syntheses (4 steps in the case of the pregnenolone, 5 steps in the case of the progesterone) whereby nitromethane under basic conditions is first added to l6-dehydropregnenolone 3-acetate via a Michael reaction, followed by ketalization of the keto group of the l6a-nitromethyI-5-pregnen-3B-ol-20 -one 3-acetate thereby formed. The resulting 16w nitromethyl-ZO-ethylenedioxy-5-pregnen-3/3-ol-20-one 3-acetate upon reduction followed by hydrolysis of the 20ketal function yields the required 16maminomethyl-5-pregnen-3fi-ol-20-one (i.e. 160taminomethylpregnenolone) intermediate. When the 3- keto-4dehydropregnane intermediate is desired, the E aforementioned loa-aminomethylpregnenolone is oxidized to obtain l6oz-aminornethylprogesterone. Alternatively, the 3,8-hydroxy-5-dehydro system in the 160: nitromethylpregnenolone intermediate can be oxidized to the 3-keto-4-dehydro system to form 160:- nitromethylprogesterone which can be ketalized to the 3 ,ZO-bis-ethylenedixoy-l 6a-nitromethyl-4-pregnene followed by reduction and hydrolysis to obtain 160eaminomethylprogesterone intermediate.

By the process of this invention, it is possible to prepare novel, pharmacologically active androsteno- 17a, l6a-c]-2', 5 '-dimethyl-5 -alkyl -l '-pyrrolines (which cannot be prepared from the aforementioned prior art products) from the corresponding 3-lceto- 4,16-bis-dehydroand 3fi-acetoxy -5 l 6'bisdehydropregnanes in only two reaction steps. By my process a l6-dehydropregnane (e.g. 3B-acetoxy-S,l6-

pregnadien-ZO-one) upon treatment with a disubstituted methylamine (e.g. isopropylamine) in the presence of of light in the wave length range of from about 2,200 A to about 3,500 A surprisingly yields a l6a-( l-amino-l '-alkylethyl)-pregnane (e.g. I6a-( 1'- amino-l "methylethyl)-5-pregnen-3B-ol-20 one 3- acetate) which upon mild treatment with a secondary or tertiary amine in a lower alkanoic acid (e. g. pyridine 0 and acetic acid) yields an androsteno-[ 17a, l6a-c]-2',

5 -dimethyl-5 '-aIkyl-l '-pyrroline heretofore unknown in the art and having pharmacological activity.

In the first step of my process, addition of a primary alkyl amine (e. g. isopropylamine or sec.-butylamine) to the double bond at 0-16 yields a l6a-aminoalkyl derivative which is attached to the steroid nucleus through a carbon-carbon bond, e.g. to yield a amino-isopropyl derivative (also named l6a-( lamino-1'-methyI-ethyl) or a I6a-amino-sec.-butyl derivative (also named l6a-( l'-amino-l '-ethylethyl) respectively. This is surprising since it is known that reaction of a 16-pregnene with primary amines such as isopropylamine or sec.-butylamine, for example, results in addition through a nitrogen-caribou bond producing l6-alkylamino derivatives such as l6a-isopropylamino or 16a-sec.-butylarnino-pregnenes, respectively.

It is also surprising that in the second step of my process it is possible to effect ring closure of the hindered l6a-(l'-amino-l-alkylethyl)-pregnene derivative under such mild conditions in view of prior art methods which require strong base.

Additionally, from the teaching in the art, it is apparent that the novel androsteno[l7a,l6a-c]-2',5'- dimethyl-5-aIkyl-l'-pyrrolines of this invention could not be prepared from the prior art 5 '-unsubstituted pyrrolines because selective alkylation at the 5' carbon could not be accomplished; rather, there would occur prior alkylation at C-2l and/or C-l7 with ring cleavage.

Thus, by my invention, a'novel process produces a novel class of compounds having pharmacological activity.

SUMMARY OF THE INVENTION The invention sought to be patented in a composition-of-matter aspect resides in the concept of a chemical compound having mild stimulant activity which has a molecular structure comprising an androsteno- [l7a,l6-c]-2', 5'-dimethyl-l'-pyrroline nucleus with a double bond stemming from C-S and an oxygen function at C-3 of the androstene portion thereof and also having a second alkyl substituent at C--5 of the pyrroline ring selected from the group consisting of methyl, ethyl, and benzyl. Also included in my inven tion are the pharmaceutically acceptable acid addition and alkyl halide quaternary salts thereof.

The invention sought to be patented in another composition-of-matter aspect resides in the concept of a chemical compound useful mainly as an intermediate which has a molecular structure comprising a pregnen- 20-one nucleus with a double bond stemming from C- 5, an oxygen function at C-3, and a 16a-( 1 '-aminol alkylethyl) substituent wherein said l'-alkyl is selected from the group consisting of methyl, ethyl, and benzyl.

The invention sought to be patented in the process aspect of this invention resides in the concept of treat ing a l6-dehydro-20-ketopregnane selected from the alkyl is a member selected from the group consisting of l 5 methyl, ethyl, and benzyl, said l6a-aminoalkylpregnanes being useful as intermediates and also being pharmacologically active. The process aspect of this invention also includes the concept of treating said aforedescribed l6a-aminoalkylpregnanes with an amine selected from the group consisting of a secondary and a tertiary amine in the presence of a lower alkanoic acid, and when said secondary amine is reacted with a lfi-aminoalkylpregnane having a 3-keto-4- dehydro system, treating the product thereby formed with dilute acid, whereby is formed an androstenopyrroline selected from the group consisting of 3-keto-4- androsteno-[ 1 7a, 1 6a-c ]-2',5 -dimethyl-5 '-alkyl-l pyrroline and 3fi-OR-5-androsteno-[l7a,16a-c]-2',5- dimethyl-5'-alkyl-1'-pyrroline wherein R and alkyl are as hereinabove defined, said androstenopyrrolines having mild stimulant activity.

GENERAL DESCRIPTION OF THE INVENTION Composition-of-Matter Aspect Included among the physical embodiments of the pharmacologically active composition-of-matter aspect of this invention are androstenopyrrolines selected from the group consisting of 4-androstenes and 5-androstenes of the following structural formula I:

ing of methyl, ethyl, and benzyl, and Z is a member selected from the group consisting of wherein R is a member selected from the group consisting of hydrogen and lower alkanoyl; and, the pharmaceutically acceptable acid addition salts and lower alkyl halide quaternary salts thereof.

The compounds of formula I wherein X is ethyl or benzyl have a new asymetric center at C-5' due to which the compounds exist in two epimeric forms, both of which are included within my inventive concept. The physical embodiment of the compounds of formula I wherein X is ethyl or benzyl are manufactured and utilized as an epimeric mixture. In the specification and in claims of this application, the name of a compound wherein X is ethyl or benzyl includes both epimeric forms. Thus, the name 3B-acetoxy-5-androsteno- 17a, l6-c]-2',5'-dimethyl-5'-ethyll -pyrroline implicitly includes both epimeric forms at C-5'.

The lower alkanoyl groups included within the substituent R are preferably derived from lower alkanoic acids having up to 8 carbon atoms including acetic, propionic, n-butyric, iso-butyric, trimethylacetic, valeric, iso-valeric, caproic, and caprylic acid.

In this specification, the term alkyl includes benzyl (i.e. phenylmethyl) as well as methyl, ethyl and the like.

The androstenopyrrolines of this invention are named in accordance with accepted practice. As shown in formula I hereinabove, the numbering of the carbon atoms in the steroidal nucleus is that well known in the art; the numbering of positions in the pyrroline nucleus begins with the nitrogen atom and goes counterclockwise so that the carbons numbered 3 and 4' in the pyrrolidene ring are the same carbon atoms numbered l7 and 16, respectively, in the steroid nucleus. Additionally, in accordance with accepted practice for fused ring systems, the bond between the l and 2 positions of the pyrroline nucleus is identified as a, that between the 2 and 3 positions as b, etc. Thus, the common bond in the fused ring system of the androstenopyrrolines of this invention is the 0 bond and the compounds are named as androsteno-[ 1701, 1 601-0]- 1 '-pyrrolines.

Preferred compounds of formula I are those wherein X is methyl, particularly those compounds wherein Z is the compound wherein R is acetoxy, being particularly valuable, said compound being 3l3-acetoxy-5-androsten0-[ l 6a-c]-2',S',5' l '-pyrroline.

Illustrative of other compounds defined by formula I are 3-keto-4-androsteno-[ 1 7a, 1 6a-c]-2,5 ,5 trimethyl-l '-pyrroline; 3B-acetoxy-5 androsteno- 17a, 1 6-c]-2',5 -dimethyl-5'-benzyll '-pyrroline; 3- keto-4-androsteno-[ 17a, 1 6a-c ]-2' ,5'-dimethyl-5 benzyll '-pyrroline; 3B-acetoxy-5-androsteno-[ 1 7a, 1 6 a-c]-2' ,5 -dimethyl-5'-ethyl-l '-pyrroline; and 3-keto- 4-androsteno-[ 1 7oz, 1601-01-2 ,5 '-dimethyl-5 '-ethyl-l pyrroline.

The androstenopyrrolines of formula I are mild stimulants making them valuable in alleviating depression and/or fatigue, in the treatment of narcolepsy, and as an aid in performance enhancement.

Additionally, the 3B-lower alkanoyloxy-S-pregnenes of formula I (i.e. those wherein Z is are aids in memory enhancement as demonstrated by their ability to accelerate the rate of acquisition of an avoidance response by mice.

in addition to the foregoing, the 3B-lower alkanoyloxy-S-androstenopyrrolines of this invention exhibit anti-inflammatory activity, this making them of value in the treatment of inflammatory states.

The compounds of formula I may be used as medicaments in conditions requiring a mild stimulant and can be administered to mammals orally, the dose administered beingdependent on the size and age of mammal, and the severity of the condition being treated.

Also contemplated as within the composition-ofmatter aspect of this invention are pharmaceutically acceptable acid addition salts of the androstenopyrrolines of formula I, which can be made according to known procedures by neutralizing the free base with the appropriate acid. Suitable acids for this purpose are such as hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, maleic, and the like.

The physical embodiments of the acid addition salts of the androstenopyrrolines of formula I are generally characterized by being white to off-white solids which are usually soluble in water and to some degree in lower alkanols, e.g. methanol and ethanol, and are insoluble in most organic solvents. In general, the acid addition salts possess pharmacological activity similar to that possessed by the parent free base and are administered in a manner similar to that of the free base. The acid addition salts may also be used as an intermediate in the purification of the androstenopyrrolines of formula I, the androstenopyrrolines being precipitated from an organic solvent (e.g. ether) by the addition of acid, and the acid addition salt thus prepared, after isolation and recrystallization, can be converted to the pure free base by addition of dilute sodium hydroxide to an aqueous solution of the acid addition salt, whereby the purified androstenopyrroline of formula I separates as a solid.

Also included within the composition-of-matter aspect of this invention are the pharmaceutically acceptable alkyl halide salts of the androstenopyrrolines of formula I, e.g. the methyl iodide, methyl chloride, and methyl bromide quaternary salts. These are prepared from the corresponding free base utilizing known techniques such as treatment of an androstenopyrroline (e.g. 3B-acetoxy-5-androsteno- [17a,l6-c]-2',5',5'l'-pyrroline) in either with an alkyl halide, e.g. methyl iodide for several hours, preferably in the dark. The methyl iodide quaternary salts thereby formed, e.g. 3B-acetoxy-5-androsteno-[ 17a, 1 6a-c]- l ',2',5,5 '-tetramethyll -pyrrolinium iodide is isolated and purified utilizing known techniques.

The alkyl halide quaternary salts of the 4-androsteno-pyrrolines of formula I possess antibacterial activity and, as such, are useful to clean and sterilize laboratory glassware and surgical instruments, and may also be used in combination with soaps, detergents, and wash solutions for sanitation purposes as in the washing of hands, and in the cleaning and sanitizing of hospital rooms and areas used for food preparationsuch as kitchens, dining halls and the like.

Additionally, the alkyl halide quaternary salts of the 3-lower alkanoyloxy-S-androstenopyrrolines of formula 1 are hypotensive agents and, as such, are useful for treatment of hypertension.

The physical embodiments of the compounds of this invention which are useful as intermediates include loa-aminoalkylpregnenes selected from the group consisting of 4-pregnenes and S-pregnenes of the following formula ll:

wherein X is a member selected from the group consisting of methyl, ethyl, and benzyl, and Z is a member selected from the group consisting of R being a member selected from the group consisting of hydrogen and lower alkanoyl; and the acid addition salts thereof.

The compounds defined by formula ll are useful mainly as intermediates in the process aspect of my invention as described in detail hereinbelow, the preferred compounds being those compounds of formula ll wherein X is methyl, particularly those wherein Z is macologically active per se exhibiting antibacterial and anti-inflammatory activity.

Included within the inventive concept are the acid addition salts of compounds of formula II which have activities similar to those of the free base and which may also be used as intermediates in purifying the 160:- aminoalkylpregnanes of formula II in the same manner as described hereinabove for the acid addition salts of the androstenopyrrolines of formula I.

PROCESS ASPECT OF THIS INVENTION The process aspect of this invention provides a method for preparing novel l6a-(l'-amino-l'-alkylethyl) pregnanes of formula II which comprises treating a l6-dehydro-20ketopregnane selected from the group consisting of 4,16-pregnadiene-3,20-dione and BB-OR-S,l6-pregnadien-20-one wherein R is a member selected from the group consisting of hydrogen and lower alkanoyl, in the presence of light, with a di'substituted methylamine selected from the group consisting of isopropylamine, sec.-butylamine, and a-methylphenethylamine.

In my process, which comprises the photochemical addition of a primary amine to a l6-dehydro bond in a A -20-keto-steroid, the amine adds to the steroid through a carbon-carbon bond (i.e. through the carbon bearing the amine function) to form a l6a-aminoalkyl derivative. This is surprising in view of the prior art teaching that a primary amine adds to a A -20-ketosteroid through a carbon-nitrogen bond (i.e. the primary amine adds at the nitrogen end) to form a l6a-alkylamino steroidal derivative.

The process aspect of this invention also provides a method for converting the novel l6a-( l -amino-l'-alkylethyl) pregnane intermediates of formula II in one step'to the novel, pharmacologically active androsteno- [l7a,16-c]-pyrrolines of formula I which comprises treating said 16a-( l-amino-l -alkylethyl)-pregnene of formula I with an amine selected from the group consisting of secondary amine and a tertiary amine in the presence of a lower alkanoic acid (preferably acetic acid) and, where a secondary amine is reacted with a 3- keto-4-dehydro intermediate, treating the product thereby formed with dilute acid, whereby is formed an androsteno-[ 1 701,1 6a-c]-3 ',5 '-dimethyl-5 '-substitutedl-pyrroline of formula I. This step of our process, which comprises isomerization of the acetyl function at Cl7 together with an intramolecular condensation via dehydration involving the hydrogens on the nitrogen of the hindered, disubstituted methylamine and the 20-keto function, takes places under mild reaction conditions (i.e. essentially neutral conditions at about 100C). This is surprising when one considers the prior art condensation of a l6a-aminoethyl5-pregnen- 20-one (wherein the aminoalkyl group is unsubstituted and thus unhindered) which utilizes a strong base (i.e. potassium t.-butoixde) as condensing agent to form the prior art androsteno-S ,5-unsubstitutedl-pyrrolines.

My process is usually carried out by dissolving the l6-dehydropregnane starting steroid (e.g. l6- dehydroprogesterone or ltS-dehydropregnenolone acetate) in a disubstituted-methylamine (e.g. isopropylamine, sec.-butylamine, or amethylphenethylamine) and, while the solution is preferably under an inert atmosphere (e.g. argon or nitrogen), irradiating the solution at room temperature with a Hanovia 200 watt high-pressure lamp in a quartz vessel for no more than about two hours, then immediately distilling the primary amine from the reaction mixture at steambath temperatures (about kylethyl)pregnene of formula II is conveniently isolated from the residue by dissolving the residue in an organic solvent immiscible with water, e.g. ether, followed by treatment of the organic solvent with an acid (e.g. hydrochloric acid) whereby the acid addition salt of a compound of formula II is formed and remains in water solution and the impurities remain in the organic solution. Isolation of the free amine of formula II is then easily effected by adding a base such as dilute aqueous sodium hydroxide until the solution is slightly alkaline whereby the l6a-aminoalkylpregnane of formula II separates as a solid which is then purified utilizing known methods such as crystallization and chromatographic techniques.

In carrying out the physical embodiment of this step of my process, the addition takes place with greatest speed and in greatest yield when irradiated with light in wave lengths of from about 2,200 A to about 3,500 A, such as supplied by a Hanovia 200 watt high-pressure lamp. The addition reaction is usually essentially complete within about 2 hours. In view of this relatively short reaction time and the immediate removal of the excess primary amine, there is eliminated the possible competing Michael reaction which is not catalyzed by light.

In this step of my process, the primary disubstitutedmethylamine reagent advantageously also serves as solvent. An organic inert solvent, e.g. benzene, acetone and hexane, may also be employed, although the presence of a solvent tends to slow the rate of the addition reaction.

The photochemical addition step is preferably carried out at room temperature (i.e. around 25 C), although the reaction may be carried out at temperatures in the range of from 0 C to about 50 C.

In carrying out the physical embodiment of the second step of my process (i.e. the isomerization and cyclization step) the 16a-(l-amino-l '-alkylethyl)- pregnen-ZO-one of formula II is usually dissolved in an ethereal solvent (such as dioxane, tetrahydrofuran, 1,2- dimethoxyethane and the like) together with a secondary amine (e.g. piperidine, pyrrolidone, and morpholine), or preferably a tertiary amine such as trimethylamine, N-methylmorpholine, and preferably pyridine. A lower alkanoic acid (usually acetic acid) is added to the reaction mixture preferably in an amount equimolar to that of the amine, and the resulting essentially neutral reaction mixture is heated at reflux temperatures for about 18 hours or until no starting material is present as evidenced by thin layer chromatographic data. The resultant cyclized product, ie an androsteno-[ l701,16a-c]-2,5'-dimethyl-5 -alkyl-l '-pyrroline of formula I is usually conveniently isolated by pouring the reaction mixture into water and separating the product either by filtration or extraction followed by purification via recrystallization or chromatographic techniques.

In carrying out the physical embodiment of this step of my process, best yields are obtained when the molar lnlnAn quantities of secondary or tertiary amine are about equimolar to that of the alkanoic acid present so that the reaction mixture is essentially neutral. While the highest yields are obtained in essentially neutral media, the quantities of lower alkanoic acid and mild base need not be equivalent to form an androsteno-pyrroline of formula I.

It is believed the presence of the mild basic medium supplied by a secondary or tertiary amine sets up an equilibrium between the l7 3-acetyl function of the l6a-aminoalkylpregnane and the l7a-acetyl epimer thereof, while thepresence of the mild acid promotes cyclization via dehydration at C20 of the l7a-acetyl epimeric form in the equilibrium mixture of the epimers at -17. I have found that if thereaction mixture is made strongly basic, a compound of formula ll will not cyclize to produce a compound of formula I in isolatable quantities. When the basic reagent is a mild base such as a secondary or tertiary amine, in accordance with my process, cyclization occurs in good yield to form a pyrroline of formula I.

The lower alkanoic acids which are conveniently used in my process are those derived from alkanoic acids having up to 8 carbon atoms such as caprylic, trimethyl acetic, butyric, propionic, and, preferably acetic acid.

When l6a-( 1 '-amino- 1 '-alkylethyl)-pregnenes of formula II having a 3-keto-4-dehydro-system are the starting compounds for the second step of my process, it is preferably to utilize a tertiary amine in the cyclization step of my process, since the use of a secondary amine such as piperidine will result in the formation of eneamines at 0-3, necessitating addition of dilute acid such as aqueous acetic acid, aqueous hydrochloric acid, aqueous perchloric acid to hydrolyze the eneamine and regenerate the free 3-keto-4-dehydro- Y i system.

A preferred method of carrying out my inventive process is that utilizing isopropylamine in the first step roline which is isolated by addition of water to the reaction mixture followed by filtration or extraction of the insoluble fraction and purification thereof utilizing methods known in the art such as crystallization or chromatographic techniques.

since thereby are prepared the preferred intermediates of formula ll, i.e. the l6a(l'-amino-l'-methylethyl)- pregnane-20-ones which upon treatment with a mixture of a weak acid and weak base according to the second step of my process will lead to the preferred androsteno-[ 17a, 1 6a-c]-2',5 ,5 l '-pyrroline of formula I.

in one preferred mode of the physical embodiment of the process aspect of my invention, 3,13-acetoxy-5, l 6- pregnadien-ZO-one in a large molar excess of isopropylamine, (e.g. over 500 molar excess) while under an atmosphere of nitrogen, is irradiated with a Hanovia 200 watt high-pressure lamp until most of the starting compound has reacted (preferably no more than about 2 hours). isolation of the resultant 3B- acetoxy- 1 6a-( 1 '-amino-l -methylethyl)-5-pregnen-20 -one of formula II is effected by immediately distilling olf at low temperatures the excess isopropylamine dissolving the residue in ether and extracting with dilute aqueous acid (e.g. 1 percent hydrochloric acid) followed by neutralization of the acid solution by the addition of base (e.g. 5 percent sodium hydroxide) and collection of the 3,B-acetoxy-l6a-(l'-amino-lmethylethyl)-5-pregnen-20 -one by filtration. Purification is effected by crystallization in known manner.

The methods of carrying out my inventive process are illustrated in the examples which follow. It is understood, that obvious modifications of my process which will be suggested by these examples to one skilled in the art, are encompassed within this inventive concept. It is understood further that my invention is limited only by my claims set forth hereinbelow.

EXAMPLE 1 3-Keto-4-androsteno-[ 17a, 1 6a-c ]-2' ,5 ',5 '-trimethyl- 1'-pyrroline A. l6a-( l -Amino-l -methylethyl)-4-pregnene-3,20- dione Irradiate a solution of 6.4 g. of 4,16-pregnadiene- 3,20-dione in 175 ml. of isopropylamine under an atmosphere of nitrogen for 2 hours with a Hanovia 200 watt high-pressure lamp in a quartz vessel. Immediately evaporate the isopropylamine at steam bath temperature and dissolve the resultant residue in ethyl ether. Extract the ethereal solution with four ml. portions of 1N hydrochloric acid solution. Combine the hydrochloric acid extracts and add 10 percent aqueous sodium hydroxide until the solution. is basic. Extract the resultant basic mixture with ethyl ether-ethyl acetate l:1 Combine the organic solutions and dry over sodium sulfate and concentrate in vacuo to a small volume, cool and filter the resultant crystalline precipitate comprising l6a-( l '-amino-l '-methylethyl)-4-pregnene- 3,20-dione.

Purify, by recrystallization from methylene chloride iso-propylether to yield 3.56 g. of l6a-(l'-amino-l'- methylethyl)-4-pregnene-3,20-dione, m.p. C; [c11 +126. l (chloroform).

B. 3-Keto4-androsteno-[ 7a, 1 6a-c]-2',5 ,5 trimethyl-l '-pyrroline To a solution of 1.2 g. of 16a-( 1 '-amino-l methylethyl)-4-pregnene-3,20-dione in 50 ml. dioxane, add 0.485 ml. of pyridine and 0.342 ml. of acetic acid. Heat the solution at reflux temperature for 12 hours; then pour the reaction mixture onto a mixture of ice and water containing sodium bicarbonate and sodium chloride. Collect by filtration, wash and dry the resultant precipitate comprising 880 mg. of 3-keto-4- androsteno-[ 17a, l6a-c]-2,5,5 '-trimethyl-l '-pyrroline. Purify further by crystallization from ether, m.p. l50- 152C; [01],, 4l.5(dioxane).

EXAMPLE 2 and the Corresponding 3hydroxy Derivative A. l6a-( l-Amino-l -methylethyl)-5-pregnen-3B-ol- 20-one 3-acetate lrradiate a solution of g. of 4,16-pregnadien-3B- ol--one S-acetate in 200 ml. of isopropylarnine under an atmosphere of nitrogen for two hours a Hanovia 200 watt high-pressure lamp in a quartz vessel. Immediately evaporate the isopropylamine at steam bath temperature. Dissolve the resultant residue in about 375 ml. of ether and extract the ethereal solution with 1 percent hydrochloric acid solution (about 375 ml.). Add 5 percent aqueous sodium hydroxide to the hydrochloric acid extract until the extract is slightly basic. Collect the resultant precipitate by filtration and wash and air dry the precipitate comprising l6a-(1'-amino-1- methylethyl)-5-pregnen-3B-ol-20-one 3-acetate. Purify by crystallization from methylene chloride-acetone hexane, m.p. 165 170C; [01],, +1 .6 (dioxane). B. 3B-Acetoxy-S-anQostgojj 701,1 6 a c]-2 ,5 ,5 trimethyl l-pyrroline and the corresponding 3]} hydroxy derivative ',5,5 %-trimethyI-I-pyrroline. Purify by chroma-,

tographing the precipitate over silica gel (18 2.5 cm.) eluting with methylene chloride. Evaporate the combined methylene chloride eluates and crystallize the resultant residue from methylene chloride-hexane to obtain 3B-acetoxy-5-androsteno-[17a,16a-c]-2,5, 51-pyrroline, m.p. 17l174 C; [a]D -'*-135.2 (dioxane).

2. Alternatively, the compound of this example and the 3B-hydroxy derivative thereof are prepared as fol lows: To a solution of 6.24 g. of 16a-( l'-amino-l'- methylethyl)-5-pregnen-3,B-ol-20-one 3-acetate in 100 ml. of dioxane, add 2.79 ml. of piperidine and 1.81 ml. of glacial acetic acid. Heat the solution at reflux temperature for 3 days, then pour into a large volume of water. Collect the resultant precipitate by filtration and extract the aqueous filtrate with methylene chloride. Combine the methylene chloride extracts with the precipitate and chromatograph the methylene chloride solution over silica gel eluting with methylene chlorideethyl acetate 9:1 Combine the eluates and evaporate to a residue; then recrystallize the residue from ethyl acetate methanol to obtain 3.8 g. of 3/3-acetoxy-5-androsteno-[ l 7a,16a-c]-2',5',5'l '-pyrroline.

The 3B-hydroxy compound is obtained by eluting the silica gel column a second time with methylene chloride-ethyl acetate (1:1). Combine the eluates and evaporate to a residue comprising 160 mgm. of 3B l-pyrroline. Purify by recrystallization from methylene 12 chloride-hexane, m.p.=235-241 C; [01],, 147.3 (dioxane).

EXAMPLE 3 3,B-Acetoxy-5-androsteno-[ 1 7a, 1 6a-c]-l ,2',5 ,5- tetramethyl- 1 '-pyrrolinium iodide To a solution of 500 mgm. of 3B-acetoxy-5-androsteno-[ 17a, 1 6a-c]-2',5',5 l -pyrroline in 50 ml. of ether, add 9 ml. of methyl iodide. Stir the reaction mixture for two days at room temperature. Collect the resultant precipitate by filtration to obtain 609 mgm. of 3B-acetoxy-5-androsteno-[l7a,l6a-c]-l ',2,5-tetramethyl-1-pyrrolinium iodide. Purify by crystallization from methanol-ether, m.p.=255 260C (decomposition); [(11 -54.6(dioxane).

EXAMPLE 4 3-Keto-4-androsteno-[ 1 7a, 1 6a-c1-l ',2',5 ,5- tetramethyll '-pyrrolinium iodide To a solution of 300 mgm. of 3-keto-4-androsteno-[ l7a,l6a]-2',5',5'-trimethyl-l'-pyrroline in 50 ml. of ether, add 6 ml. of methyl iodide and stir the reaction mixture in the dark for six hours. Collect the resultant precipitate by filtration and wash the precipitate with ether and air dry to give 210 mgm. of 3-keto-4-androsteno- [170a, l 6a-c]-l ',2',5 ,5'-tetra-methyl-l '-pyrrolinium iodide, [(11 3 8 (dioxane).

EXAMPLE 5 3B-Acetoxy-5-androsteno-[ 17a, 1 6a-c ]-2,5 -dimethyl- 5 -benzyl l -pyrroline and the Methyl Iodide Quaternary Salt Thereof A. l6a-( 1 '-Aminol -benzylethyl)-5-pregnen-3B-ol- 20-one 3-acetate lrradiate a solution of 10 g. of 5,16-pregnadien-3/3- ol-20-one 3-acetate in 200 ml. of amethylphenethylamine under nitrogen for 2 hours with a Hanovia 200 watt high-pressure lamp in a quartz vessel. Immediately distill the a-methylphenethyl-amine in vacuo. Dissolve the resultant residue in 400 ml. of ether and extract with a 1 percent hydrochloric acid solution. Add 5 percent sodium hydroxide to the hydrochloric acid extract until the solution is alkaline. Collect by filtration and dry the resultant precipitate to obtain 16a- 1 '-amino-1 '-benzylethyl)-5-pregnen-3B-ol-20-one 3- acetate. Purify by crystallization from ethyl acetatehexane. B. 3B-Acetoxy-5-androsteno-[ 17a, 1 6a-c]-2' ,5 dimethyl-S -benzyll '-pyrroline To a solution of 3 g. of l6a-( l '-amino-l benzylethyl)-5-pregnen-3B-ol-20-one 3-acetate in ml. of dioxane, add 1.24 ml. of piperidine and 0.76 ml. of acetate acid. Heat the reaction mixture at reflux temperature for 17 hours. Concentrate the reaction mixture in vacuo to a volume of about 20 ml., then add to ice water. Collect by filtration and air dry the resultant precipitate. Purify the precipitate by chrol3 matography over silica gel eluting with methylene chloride. Combine the methylene chloride eluates, evaporate to a residue, then crystallize the resultant residue from acetone-hexane to give 3B-acetoxy-5-androsteno-[ 1 7a, l6a-c]-2',5-dimethyl-5 '-benzyl-l '-pyrroline. C. 3B-Acetoxy-5-androsteno-[l7a,16a-c]-1 ,2 ,5 trimethyl-5-benzyl lpyrrolinium iodide To a solution of 500 mgm. of 3B-acetoxy-5-androsteno- 17a, 1 6a-c1-2' ,5-dimethyl-5 '-benzyll '-pyrroline in 40 ml. of ether, add ml. of methyl iodide. Stir the reaction mixture in the dark for hours. Collect the result precipitate by filtration, wash the precipitate with ether and air dry to give 3B-acetoxy-5-androsteno- 17a, 1 6-c]- l ,2',5'5'-benzyll '-pyrrolinium iodide.

EXAMPLE 6 3-Keto-4-androsteno-[ 1 7a, 1 6a-c]-2 ,5 '-dimethyl-5'- bepzyll '-pyrroline and the Methyl lodide Quaternary Salt Thereof A. l6a-( l '-Amino-1'-benzylethyl)-4-pregnene-3 ,20- dione lrradiate a solution of 5 g. of 4,1 6-pregnadiene-3,20 dione in 200 ml. of a-methylphenethylarnine under nitrogen for 90 minutes with a Hanovia 200 watt highpressure lamp in a quartz vessel. Immediately distill the a-methylphenethylamine in vacuo. Dissolve the resultant residue. in ether and extract with a 1 percent hydrochloric acid solution. Add 10 percent sodium hydroxide until the hydrochloric acid extract becomes alkaline. Extract the aqueous alkaline mixture with ether and ethyl acetate. Combine the organic extracts, dry over sodium sulphate, and concentrate to small volume. Crystallize the residue from ethyl acetate-hexane to obtain 16a-(1'-amino-l'-benzylethyl)-4- pregnene-3,20-dione. B. 3-Keto-4-androsteno-[ 1 7a, 1 6a-c]-2' ,5 '-dimethyl-5 -benzy1-lpyrroline To a solution of 900 mgm. of l6a-( l'-amino-l'- benzylethyl)-4-pregnene-3,20-dione in 40 ml. of dioxane, add 0.37 ml. of pyridine and 0.26 ml. of acetic acid. Heat the reaction mixture for 18 hours at reflux temperature. Concentrate in vacuo to a volume of about 20 ml., then add to ice water. Collect the resultant precipitate by filtration, wash with water, then dry the precipitate to obtain 3-keto-4-androsteno-[ 1 70:, l 6011-2,5-dimethyl-5'-benzyl-l '-pyrroline. Purify by crystallization from ethyl acetate. C. 3-Keto-4-androsteno-[ 17a, 1 6a-c]-l ',2',5'- trimethyl-5'-benzyl- 1 '-pyrrolinium iodide To a solution of 360 mgm. of 3-keto-4-androsteno-[ 17a, 1 6a]-2 ,5-dimethyl-5 -benzyll '-pyrroline in 55 ml. of ether, add 8 ml. of methyl iodide. Stir the reaction mixture in the dark for 7 hours, then collect the resultant precipitate by filtration. Wash the precipitate with ether and air-dry to obtain 3-keto-4-androsteno-[ 1 7a, 1 6a] 1 ,2 ,5 -trimethyl-5 '-benzyl-l '-pyrrolinium iodide.

14 EXAMPLE 7 l'-pyrroline and the Methyl lodide Quaternary Salt Thereof A. l6a-(l '-Amino-1 -ethylethyl)-5 -pregnen-3 13-01-20- one 3-acetate lrradiate a solution of 7.5 g. of 3B-acetoxy-5,l6- pregnadien-ZO-one in 200 ml. of sec.-butylamine under nitrogen for two hours with a Hanovia 200 watt highpressure lamp in a quartz vessel. Evaporate the sec-butylamine rapidly, dissolve the resultant residue in ether, then extract the ethereal solution with a 1 percent hydrochloric acid solution. Add 10 percent sodium hydroxide to the hydrochloric acid. extracts until the solution is alkaline. Extract the alkaline solution with ethyl acetate, dry the combined organic extracts over sodium sulphate, then concentrate to a low volume and crystallize by addition of hexane to obtain l6a-(l'- amino-l'-ethylethyl)-5-pregnen-3B-ol-20-one 3 acetate. B. 3B-Acetoxy-5 -androsteno-[ 1 7a, 1 6a-c]-2 ,5 dimethyl-5'-ethyll'-pyrroline To a solution of 720 mgm. of BB-acetoxy-S-androsteno-[ 17a,l6a-c]-2',5-dimethyl-5 '-ethyll -pyrroline in 80 m1. of ether, add 10 ml. of methyl iodide. Stir the reaction mixture in the dark for 24 hours, then add 10 ml. of additional methyl iodide and continue stirring for 2 more days. Pour off the supernatant liquid, and triturate the gummy residue with isopropyl ether. Collect the resultant amorphous solid by filtrarr tion, wash the solid with ether, then air dry to obtain BQ-acetoxy-S-androsteno-[17a,l6a-c}-1,2',5'trimethyl-5'-ethyl-l -pyrrolinium iodlide.

EXAMPLE 8 I 3-Keto-4-androsteno-[ 17a, 1 6a-c]-2',5 '-dimethyl-5 ethyll -pyrroline and the Methyl lodide Quaternary Salt Thereof tract the resultant basic mixture with ethyl acetate, dry the combined extracts over sodium sulphate, then evaporate to a small volume. Crystallize the resultant residue from ethyl acetate-hexane to obtain 16a-( 1'- aminol -ethylethyl )-4-pregnene-3,20-dione. B. 3-Keto-4-androsteno-[ 1 701,1 6a-c]-2',5-dimethyl-5 -ethyl-l pyrroline To a solution of 670 mgm. of l6a-(1'-amino-1- ethylethyl)-4-pregnene-3,20-dione in 35 ml. of dioxane, add 0.29 ml. of pyridine and 0.19 ml. of acetic acid. Heat the reaction mixture at reflux temperature for 17 hours. Add the reaction mixture to ice water, collect the resultant precipitate by filtration, wash with water, and dry. Purify the resultant precipitate by crystallization from ether-isopropyl ether to obtain 3- keto-4-androsteno-[ l7a,16a-c]-2 ,5 '-dimethyl-5 ethyl-l -pyrroline. C. 3-Keto-4-androsteno-[ 17a, 1 6a-c]- l ',2',5- trimethyl-5-ethyll -pyrrolinium iodide v To a solution of 500 mgm. of 3-keto-4-androsteno-[ 17a, 1 6111-2 ,5-dimethyl-5 -ethyl-l '-pyrroline in 40. ml. of dry tetrahydrofuran, add ml. of methyl iodide. Stir the reaction mixture in the dark for 6 hours. Collect the resultant precipitate by filtration, wash the precipitate with tetrahydrofuran, and dry to obtain 3- keto-4-androsteno[ 17a, 1 6a-c]- l ,2',5-trimethyl-5- ethyl-l '-pyrrolinium iodide.

EXAMPLE 9 l6a-( l '-dimethylamino-l '-methylethyl)-5-pregnene- 3,B-ol-20-one- 3-acetate To a solution of 831 mgm. of l6a-(l'-amino-l'- methyl-ethyl)-5-pregnen-3B-ol-20-one 3-acetate in 20 ml. of 90 percent formic acid, add 0.65 ml. of 35 percent formaldehyde. Heat the solution at reflux temperature for 10 hours. Add 0.4 ml. of concentrated hydrochloric acid. Evaporate the formaldehyde and formic acid in vacuo and dissolve the resultant residue in water. Add 10 percent sodium hydroxide to the aqueous solution until it is alkaline. Filter the resultant precipitate, wash with water and dry. Re-acetylate the precipitate with acetic anhydride in pyridine at room temperature according known procedures. Crystallize the resultant product from methyl alcohol-ethyl acetate to obtain l6a-( l'-dimethylamino-l -methylethyl)-5- pregnen-3/3-ol-20-one 3-acetate l6a-( l -dimethylamino-l -benzylethyl)-5-pregnen-3flol-20-one 3 -acetate To a solution of 1.978 g. of l6a-( l-amino-l'- benzylethyl)-5-pregnen-3/3-ol-20-one 3-acetate in 45 ml. of formic acid, add 1.2 ml. of 35 percent formaldehyde. Heat the solution at stem bath temperature for 12 hours. Add 0.85 ml. of concentrated hydrochloric acid, then evaporate the formaldehyde and formic acid in vacuo. Dissolve the resultant residue in water and add 2N sodium hydroxide until the solution is alkaline. Filter, wash and dry the resultant precipitate. Re-acetylate the precipitate with acetic anhydride in pyridine at room temperature according to known procedure.

Crystallize the re-acetylated material from methanol to give l6a-(l '-dimethylamino-l -benzylethyl)-5- pregnen-3B-ol-20-one 3-acetate.

EXAMPLE ll .ethyl)-4-pregnene-3,20-dione.

EXAMPLE l2 3B-Acetoxyl 6 1 '-amino- 1 '-methylethyl)-5-pregnen- 20-one hydrochloride A. Bubble anhydrous hydrogen chloride gas through a solution of 2.5 g. of 3B-acetoxy-l6a-( l -amino-l methylethyl)-5-pregnen-20-one in ml. of ether at a slow rate for about 20 minutes. Separate by filtration the resultant crystalline precipitate, then thoroughly wash the precipitate with 550 ml. of anhydrous ether and dry in vacuo to obtain 3B-acetoxy-l6a-( 1 -amino- 1 -methylethyl)-5-pregnen-20-one hydrochloride.

B. In similar manner treat each of the following with v anhydrous hydrogen chloride in ether:

16a-( 1 '-amino- 1 '-methylethyl)-4-pregnene-3,20- dione,

3fi-acetoxy- 1 6a-( 1 -amino-l -benzylethyl)-5- pregnen-ZO-one,

16a-( 1 '-amino-l '-benzylethyl)-4-pregnene-3,20- dione,

3B-acetoxy- 1 6a-( 1 '-amino-l '-ethylethyl)-5- pregnene-ZO-one, and

l6a-( 1 '-amino-] -ethylethyl) 4-pregnen-3,20-dione. Isolate and purify the resultant products in a manner similar to that described hereinabove to obtain the corresponding hydrochloride acid salts, namely,

l6a-( 1 '-aminol '-methylethyl)-4-pregnen-3 ,20- dione hydrochloride,

3/3-acetoxy- 1 6a-( 1 '-amino-l '-benzylethyl)-5- pregnen-ZO-one hydrochloride,

l6a-( l-amino-l '-benzylethyl)-4-pregnene-3,20- dione hydrochloride,

3B-acetoxy- 1 6a-( l'-amino-l -ethylethyl)-5- pregnen-ZO-one hydrochloride, and

l6a-( l '-amino-l '-ethylethyl)-4-pregnene-3,20- dione hydrochloride.

EXAMPLE 13 pyrroline hydrochloride A. Through a solution of 1.77 g. of 3B-acetoxy-5-androsteno-[l7a,l6a-c]-2',5',5'1'-pyrroline in 65 ml. of anhydrous ether, bubble dry hydrogen chloride gas for a period of about minutes. Separate the resultant white amorphous solid by filtration, wash the filtrate several times with ether, then dry in vacuo to obtain 3B-acetoxy-5-androsteno-[ 17a, 1 6a-c]-2 ',5 T ,5 -trimethy|- l -pyrroline hydrochloride. B. In similarmanner treat each of the following androsteno pyrrolines with dry hydrogen chloride gas in ether:

3-keto-4-androsteno-[ 1 7a, 1 6a-c ]-2' ,5 ,5 '-trimethyll'-pyrroline hydrochloride,

3B-acetoxy-5-androsteno-[ 17a, 1 6a-c1-2 ,5'- dimethyl-5'-benzyl-l -pyrroline,

3-keto-4-androsteno-[ 170:, l 6a-c]-2',5 -dimethyl-5 benzyl-l '-pyrroline, 3B-acetoxy-5-androsteno-[ 17a, 1 6a-c]-2',5'- dimethyl-S -ethyl-l '-pyrroline, and

3-keto-4-androsteno-[ 17a, 16a-c]-2',5'-dimethyl-5- ethyl-l '-pyrroline. Isolate and purify the resultant respective products in a manner similar to that described hereinabove to obtain, respectively,

3-keto-4-androsteno-[ 17a, l6a-c]-2,5,5'- trimethyl-l '-pyrroline hydrochloride,

3B-acetoxy-5-androsteno-[ 17a, 1 6a-c]-2',5'- dimethyl-5'-benzyl-l -pyrroline hydrochloride,

3-keto-4-androsteno-[ l701,16a c]-2,5'-dimethyl-5'- benzyl- 1 '-pyrroline hydrochloride,

3B-acetoxy-5-androsteno-[ 17a, 1 6a-c]-2',5- dimethyl-5'-ethyl-l '-pyrroline hydrochloride, and

3-keto-4-androsteno-[ l 701,16a-c]-2,5'-dimethyl-5- ethyl-l '-pyrroline hydrochloride.

lclaim: l. A compound selected from the group consisting of 4-androstenes and 5-androstenes of the following structural formula:

wherein X is a member selected from the group consisting of methyl, ethyl, and benzyl, and Z is a member selected from the group consisting of 2. A compound according to claim 1 wherein X is methyl.

3. A 4-androstene of claim 1 wherein X is methyl and Z is and said compound being 3-keto-4-androsteno-[l701,160:- c]-2',5,5'-trimethyl-l '-pyrroline.

4. A S-androstene of claim 1 wherein X is methyl and Z is O GHJ JO said compound being 3,8-acetoxy-5-androsteno- [17a,16-c]-2',5',5' l '-pyrroline.

5. A methiodide quaternary salt of a S-androsterie of claim 1 wherein X is methyl and Z is CH K 011:

wherein X is a member selected from the group consisting of methyl, ethyl, and benzyl, and Z is a member selected from the groupconsisting of CH; CH:

R being a member selected from the group consisting of hydrogen and lower alkanoyl; and the acid addition salts thereof.

7. A compound according to claim 6 wherein X is methyl.

8. A 5-pregnene compound according to claim 6 wherein X is methyl and Z is o CHag O-- 19 said compound being l6a-(l-amino-l-methylethyl)- 4-pregnen-3B-ol-20-one 3-acetate.

9. A 4-pregnene compound according to claim 6 wherein X is methyl and Z is said compound being l6a-( l-amino-l -methylethyl)- 4-pregnene-3,20-dione.

10. A process for the preparation of a l6a-aminoal kyl-pregnane of following formula 1;

and

R being a member selected from the group consisting of hydrogen and lower alkanoyl;

which comprises treating a l6dehydro-20- ketopregnane selected from the group consisting of 4,l6-pregnadiene-3,20-dione and 3B-OR-5,l6-

pregnadien-20-one wherein R is as hereinabove defined, with a di-substituted methylamine selected from the group consisting of isopropylamine, sec.-butylamine, and amethylphenethylamine in the presence of light in the wave length range of from about 2,200 A to about 3,500 A.

11. The process according to claim 10 wherein said di-substituted methylamine is isopropylamine whereby is obtained a l6a-aminoalkylpregnane of formula I wherein X is methyl.

12. The process according to claim 10 wherein said l6-dehydro-20-keto pregnene is 3B-acetoxy-5,l6- pregnadien-20-one, and said di-substituted methylamine is isopropylamine whereby is obtained 1 6a-( 1 -amino-l '-methylethyl)-5-pregnen-3,B-ol-20- one 3-acetate.

13. The process of claim 10 including the added step of treating the thereby formed la-aminoalkylpregnane of formula] with an amine selected from the group consisting of a secondary and a tertiary amine in the presence of a lower alkanoic acid, said process comprising treating a l6-dehydro-20-ketopregnane selected from the group consisting of 4,16- pregnadiene-3,20-dione and 3B-OR-5,l6-pregnadien- 20-one, R being a member selected from the group consisting of hydrogen and lower alkanoyl, with a disubstituted methylamine selected from the group consisting of sec.-butylamine, and amethylphenethylamine, in the presence of light in the wave length range of from about 2,200 A to about 3,500A, whereby is formed a l6a-alkylaminopregnane of following formula 1:

wherein X is a member selected from the group consisting of methyl, ethyl, and benzyl, and Z is a member selected from the group consisting of CH3 CH3 and R being as hereinabove defined,

and treating the thereby formed l6a-aminoalkylpregnane of formula I with an amine selected from the group consisting of a secondary and a tertiary amine in a lower alkanoic acid, and when a secondary amine is used with a compound wherein Z is treating the product thereby formed with dilute acid, whereby is formed an androstenopyrroline of following formula II:

wherein X and Z are as hereinabove defined for formula 1.

14. The process according to claim 13 wherein said amine is a tertiary amine.

15. The process according to claim 13 wherein said amine and said lower alkanoic acid are about equimolar.

16. The process according to claim 13 wherein said amine is a tertiary amine, and said lower alkanoic acid is acetic acid, and said tertiary amine and acetic acid are about equimolar.

17. The process of claim 13 wherein said 16- dehydro-20-keptopregnane is 4,l6-pregnadiene-3,20- dione, said di-substituted methylamine is isopropylamine, said amine is pyridine, and said lower alkanoicacid is acetic acid, the molar quantity of said acetic acid being about twice the molar quantity of said 21 4,16-pregnadiene-3,20-dione, said acetic acid and pyridine being equimolar, said process comprising treating 4,l6-pregnadiene-3,20-dione with isopropylamine in the presence of light in the wave length range of from about 2,200 A to about 3,500 A and treating the thereby formed l6a-(l'-amino-lmethylethyl)-4-pregnene-3,20-dione with acetic acid and pyridine, the molar quantity of acetic acid being about twice the molar quantity of said l6a-( l'-aminol'-methyl-ethyl)-4-pregnene-3,20-dione and the pyridine being about equimolar to the acetic acid, whereby is formed 3-keto-4-androsteno-2,5,5 y -thyme-Mr, a. '18; The process of claim 13 wherein said 16- dehydro-ZO-ketopregnane is 3B-acetoxy-5 l 6- pregnadien-ZO-one, said di-substituted methylamine is isopropylamine, said amine is pyridine, and said lower 291199".llllll fiflhyl YEYEEWPZP'QQE l c yri in being about equimolar to the acetic acid, whereby is formed BB-acetoxy-S-androsteno-Z' ,5 ',5 -trimethyll pyrroline.

PO-mo s'm'dss dddhsd ossdhs (5/ 9) h I v T QERWHUWEE Cd QGRMECEWN Patent: do. 5,6 +,T99 omd' August 5, 97

Inventor) Thomas L. Popper 7 It is certified that error ap pe a'rs in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

molumn 1, lines 21 and 22, "5-keton-LL-androsten" should read-- 5-keto-h-androsteno- Column line &7, "2' 5' 5' ,l'- pyrroline" should read 2',5',5'-trimethyl-l'-p rroline--; line 51, "FlTOl, 16-55;" shouldread l70, l6Q-c 4-. I Column 5,

, line 51, "T1706, 16-0 -2' 5", 5' ,l'-pyr foli ne)" should read l7 1606- c7-2' 5 5'-trimethylu-l' -p z'roline)--. Column ,6, line 1-9, "/TTOI, l6-c shouldread 1705, 1605 070; lines 50, and 51, "2' 5",5* l/ +-t 1 imethyl-l' pyrroline). should read "2' 5' 5'-trimethyl-l'-pyrroline Column 7, line 58, "[1706, l6-c7" should read /17d,16d 3 Column 8, line 6, "6o -lOObL c7" should read -6'o 1ooc)-. line 10, "organic solvent" should read --o1-ganic solution--. Column 9, line +8, "-2' 5' ,5'1-

pyrroline" should read -2 5 5'-trimethyl-l'-pyrroline-- Column 10, lines 7 and 8 "-2',5',5'l' -pyri'oline" should read --2",5',5'-trimethyl-l'-pyrroline--. Column ll,line 11, "hours a should read --hours with a. lines 55 and 56, "-2', 5' 5') l/h-trimethyl -l'-pyrroline" should read --2 5 5'-trimethy l-l'- pyrroline--; lines +1 and +2 "2',5',5'l'-pyrroline" should read -2,5',5'-trimethyl-l,"-py rroline-:-; line 61, 2',5',5'1'. pyrroline" should read --2',5','5'--trimethyl-l'-p3 '1'1"oline---- Column '12, line ll, "-2' 5' 5' l'-pyrroline" should read -2' 5?, 5'-trin1eth yl-l'pyrroline--; lines 15 and 16 "-l',2',5'-

tetramethyl" should read -l',2',5', '-tetramethyl--; lines 26 and 27 J.7d,16g7" should read 17d,16d c7--; line 65,

"acetate ac fd" should read --acetic aE id-- Column 15, line 16, "[1706, l6..c7 l' ,2' 5' 5'-be'nZyl-l' should read lT I', l6 c7- 1' ,2' 5'-t r imethyl-5'-benzyl-l'- lines 5 and 55 "l7d,l6 7" should read 170 l605-c7--; lines 60 and 61 lT(2,l6 O l 7" should read /17o:,1 ao7 lines 66 and 67 "[17d, 1'6g 7" should read l7 lTl6 lo7 Column 1 line 59, "iode" should read --iodide-- Column 15, lines 25 and 2 1- IlTOl, 1627" should read --{l7, l60lc7--. Column 16, line 62 (l-amino-" should read l"-amino- Column 17, line 7, "-2' 5' 5' ,l'-pyrroline" should read -2'-, 5 5'-trimethyl-l' pyrroline--.

@EREEFICATE W? 'QGRRECTEUN U Patent No. 5,68%799 ms August 15, 1972 Inventofl Thomas L. Popper It is certified that error appears in the shore-identified pateri t: and that said Letters Patent are hereby corrected as ,shown below:

fColumn l8, Claim 5, line 8 after the formula, land" should read Column 18, Claim h, ling 22; 1, a, 16- 7- 2' ,5 ,5 l -pyrr.oline". should read '---A 17 16 -2 -2 ,5 ,5 tr i methyl-l' -pyrrolin e. Colu r n n l8, Claim 5-, line 52, v 1 a, 16 -c7" should read 1 17 16m Column 19], Claim 8,

- line 2, -pregnen" should read p5 -pregnen Column;

20, Claim 17, line 65, "keptopreg na'ne" should read ketopregnane--. I

Signed and sealed this 22nd daybf May 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. s 1 ROBERT GOTTSCHALK Attesting Officer Commissioner of Patents 

2. A compound according to claim 1 wherein X is methyl.
 3. A 4-androstene of claim 1 wherein X is methyl and Z is said compound being 3-keto-4-androsteno-(17 Alpha ,16 Alpha -c)-2'',5'',5''-trimethyl-1''-pyrroline.
 4. A 5-androstene of claim 1 wherein X is methyl and Z is said compound being 3 Beta -acetoxy-5-androsteno-(17 Alpha ,16 Alpha -c)-2'',5'',5''-trimethyl-1''-pyrroline.
 5. A methiodide quaternary salt of a 5-androstene of claim 1 wherein X is methyl and Z is said compound being 3 Beta -acetoxy-5-androsteno-(17 Alpha ,16 Alpha -c)-1'',2'',5'',5''-tetra-methyl-1''-pyrrolinium iodide.
 6. A compound selected from the group consisting of 4-pregnenes and 5-pregnenes of the following formula:
 7. A compound according to claim 6 wherein X is methyl.
 8. A 5-pregnene compound according to claim 6 wherein X is methyl and Z is said compound being 16 Alpha -(1''-amino-1''-methylethyl)-4-pregnen-3 Beta -ol-20-one 3-acetate.
 9. A 4-pregnene compound according to claim 6 wherein X is methyl and Z is , said compound being 16 Alpha -(1''-amino-1''-methylethyl)-4-pregnene-3,20-dione.
 10. A process for the preparation of a 16 Alpha -aminoalkyl-pregnane of following formula I;
 11. The process according to claim 10 wherein said di-substituted methylamine is isopropylamine whereby is obtained a 16 Alpha -aminoalkylpregnane of formula I wherein X is methyl.
 12. The process according to claim 10 wherein said 16-dehydro-20-keto pregnene is 3 Beta -acetoxy-5,16-pregnadien-20-one, and said di-substituted methylamine is isopropylamine whereby is obtained 16 Alpha -(1''-amino-1''-methylethyl)-5-pregnen-3 Beta -ol-20-one 3-acetate.
 13. The process of claim 10 including the added step of treating the thereby formed 16 Alpha -aminoalkylpregnane of formula I with an amine selected from the group consisting of a secondary and a tertiary amine in the presence of a lower alkanoic acid, said process comprising treating a 16-dehydro-20-ketopregnane selected from the group consisting of 4,16-pregnadiene-3,20-dione and 3 Beta -OR-5,16-pregnadien-20-one, R being a member selected from the group consisting of hydrogen and lower alkanoyl, with a di-substituted methylamine selected from the group consisting of sec.-butylamine, and Alpha -methylphenethylamine, in the presence of light in the wave length range of from about 2,200 A to about 3,500A, whereby is formed a 16 Alpha -alkylaminopregnane of following formula I:
 14. The process according to claim 13 wherein said amine is a tertiary amine.
 15. The process according to claim 13 wherein said amine and said lower alkanoic acid are about equimolar.
 16. The process according to claim 13 wherein said amine is a tertiary amine, and said lower alkanoic acid is acetic acid, and said tertiary amine and acetic acid are about equimolar.
 17. The process of claim 13 wherein said 16-dehydro-20-keptopregnane is 4,16-pregnadiene-3,20-dione, said di-substituted methylamine is isopropylamine, said amine is pyridine, and said lower alkanoic acid is acetic acid, the molar quantity of said acetic acid being about twice the molar quantity of said 4,16-pregnadiene-3,20-dione, said acetic acid and pyridinE being equimolar, said process comprising treating 4,16-pregnadiene-3, 20-dione with isopropylamine in the presence of light in the wave length range of from about 2,200 A to about 3,500 A and treating the thereby formed 16 Alpha -(1''-amino-1''-methylethyl)-4-pregnene-3,20-dione with acetic acid and pyridine, the molar quantity of acetic acid being about twice the molar quantity of said 16 Alpha -(1''-amino-1''-methyl-ethyl)-4-pregnene-3,20-dione and the pyridine being about equimolar to the acetic acid, whereby is formed 3-keto-4-androsteno-2'',5'',5''-trimethyl-1''-pyrroline.
 18. The process of claim 13 wherein said 16-dehydro-20-ketopregnane is 3 Beta -acetoxy-5,16-pregnadien-20-one, said di-substituted methylamine is isopropylamine, said amine is pyridine, and said lower alkanoic acid is acetic acid, the molar quantity of said acetic acid being about twice that of said 3 Beta -acetoxy-5,16-pregnadien-20-one, said acetic acid and pyridine being about equimolar, said process comprising treating 3 Beta -acetoxy-5,16-pregnadien-20-one with isopropylamine in the presence of light in the wave length range of from about 2,200 A to about 3,500 A, and treating the thereby formed 3 Beta -acetoxy-16 Alpha -(1''-amino-1''-methylethyl)-5-pregnen-20-one with acetic acid and pyridine, the molar quantity of acetic acid being about twice that of said 3 Beta -acetoxy-16 Alpha -(1''-amino-1''-methylethyl)-5-pregnen-20-one, the pyridine being about equimolar to the acetic acid, whereby is formed 3 Beta -acetoxy-5-androsteno-2'',5'',5''-trimethyl-1''-pyrroline. 